In Silico Analysis of the Molecular-Level Impact of SMPD1 Variants on Niemann-Pick Disease Severity

Sphingomyelin phosphodiesterase (SMPD1) is a key enzyme in the sphingolipid metabolism. Genetic SMPD1 variants have been related to the Niemann-Pick lysosomal storage disorder, which has different degrees of phenotypic severity ranging from severe symptomatology involving the central nervous system (type A) to milder ones (type B). They have also been linked to neurodegenerative disorders such as Parkinson and Alzheimer. In this paper, we leveraged structural, evolutionary and stability information on SMPD1 to predict and analyze the impact of variants at the molecular level. We developed the SMPD1-ZooM algorithm, which is able to predict with good accuracy whether variants cause Niemann-Pick disease and its phenotypic severity; the predictor is freely available for download. We performed a large-scale analysis of all possible SMPD1 variants, which led us to identify protein regions that are either robust or fragile with respect to amino acid variations, and show the importance of aromatic-involving interactions in SMPD1 function and stability. Our study also revealed a good correlation between SMPD1-ZooM scores and in vitro loss of SMPD1 activity. The understanding of the molecular effects of SMPD1 variants is of crucial importance to improve genetic screening of SMPD1-related disorders and to develop personalized treatments that restore SMPD1 functionality.     

Assessing the Role of Developmental and Environmental Factors in Chemical Defence Variation in Heliconiini Butterflies

Journal of Chemical Ecology - Chemical defences in animals are both incredibly widespread and highly diverse. Yet despite the important role they play in mediating interactions between predators...     

The Crosstalk of Adipose-Derived Stem Cells (ADSC), Oxidative Stress,and Inflammation in Protective and Adaptive Responses

The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs is a major goal in repair medicine. Stem cells are classified by their potential to differentiate into functional cells. Compared with other sources, adipose-derived stem cells (ADSCs) have the advantage of being abundant and easy to obtain. ADSCs are considered to be tools for replacing, repairing, and regenerating dead or damaged cells. The capacity of ADSCs to maintain their properties depends on the balance of complex signals in their microenvironment. Their properties and the associated outcomes are in part regulated by reactive oxygen species, which mediate the oxidation-reduction state of cells as a secondary messenger. ADSC therapy has demonstrated beneficial effects, suggesting that secreted factors may provide protection. There is evidence that ADSCs secrete a number of cytokines, growth factors, and antioxidant factors into their microenvironment, thus regulating intracellular signaling pathways in neighboring cells. In this review, we introduce the roles of ADSCs in the protection of cells by modulating inflammation and immunity, and we develop their potential therapeutic properties.     

Viscosity reduction of isotonic solutions of the photosensitizer TPCS2a by cyclodextrin complexation

Meso-tetraphenyl chlorin disulphonate (TPCS_2a) is a photosensitizer (PS) particularly developed and patented for use in the technology of photochemical internalization (PCI) against cancer. TPCS_2a is known to aggregate in aqueous media even at low concentrations (≥0.1?µM) and to form a high-viscosity network at clinically relevant concentrations (mM). The aim of this work was to evaluate the effect of two hydroxypropylated cyclodextrin derivatives of beta and gamma type, respectively i.e. HPβCD and HPγCD, on the aggregation and solubilization of TPCS_2a in isotonic solutions. Samples containing micromolar concentrations of TPCS_2a were studied spectrophotometrically, while samples containing a clinical relevant concentration (10?mM?=?9?mg/ml) of TPCS_2a were evaluated by dynamic viscosity measurements. HPβCD was determined to be a more suitable solubilizer of TPCS_2a than HPγCD in aqueous media both in the absence and presence of salt. The complexation stoichiometry between TPCS_2a/HPβCD at micromolar to millimolar concentrations of TPCS_2a was determined to be 1:3 and 1:2 in the absence and presence of isotonic NaCl, respectively. The network of TPCS_2a (10?mM) was broken down in the presence of 3% w/v (=?20?mM) HPβCD, i.e. a 1:2 molar ratio between TPCS_2a and the cyclodextrin. Formation of the inclusion complex resulted in low viscosity samples both in water and in the presence of isotonic NaCl or phosphate buffered saline (PBS) at 25?°C and 37?°C.     

Approaches to Evaluate the Impact of a Small-Molecule Binder to a Noncatalytic Site of the Proteasome

Proteasome activity is crucial for cell survival and proliferation. In recent years, small molecules have been discovered that can affect the catalytic activity of the proteasome. Rather than targeting the active sites of the proteasome, it might be possible to affect ubiquitin-dependent degradation of proteins by limiting the association of the 19S regulatory particle (19S RP) with the 20S core particle (20S CP) of the proteasome. We recently described the discovery of TXS-8, a peptoid that binds to Rpn-6. Rpn-6 is a proteasome-associated protein that makes critical contacts with the 19S RP and the 20S CP. Herein, we present a general workflow to evaluate the impact of a small-molecule binder on proteasome activity by using TXS-8 as an example. This workflow contains three steps in which specific probes or overexpressed proteins in cells are used to determine whether the hydrolysis activity of the proteasome is affected. Although, in our case, TXS-8 did not affect proteasome activity, our workflow is highly amenable to studying a variety of small-molecule–proteasome subunit interactions.     

Effects of systematic work preparation meetings on safety climate and psychosocial conditions in the construction industry

The aim of this study was to evaluate the effect of an intervention comprising education and support in performing frequent and structured work preparation meetings with broad participation. Such work preparation meetings were expected to have positive effects on safety climate by emphasizing the value of safety at the work site, and on perceived influence at work. The study was a longitudinal, matched before and after questionnaire study, with six construction sites within a large Swedish construction company, randomly assigned to the intervention or the comparison group. Contrary to expectations, the intervention group reported a decrease in safety climate, while this increased in the comparison group. Perceived influence at work showed a tendency to decrease at the interventions sites. Frequent work preparation meetings may provide ample opportunity for obtaining perceptual safety climate cues. But the effect is dependent on how these meetings are performed, and what priorities are conveyed.     

The first years as independent actors in the housing market: Young households in a Swedish municipality

This study deals with young households at the beginning of their housing career. During the 1990s, a tendency of the young to leave the parental home at a later age than during previous decades was discussed. With extended education, rising housing costs and a shortage of rental housing, difficulties in finding an affordable place to live could be expected to have increased. Parental resources are of increasing importance in times of recession. The aim of this study was to follow the first steps in the housing careers of young individuals in a Swedish municipality and to investigate the time of nest-leaving and the choice of tenure for their first and second moves. Individuals aged 16–25 years in the municipality of Gävle, Sweden, were included in the study. Longitudinal data for the years 1985–1995 were used. To capture changes over time, the nest-leaving situations of two cohorts were compared. Results indicate that the individuals in the 1973 cohort leave home at a higher age than do those in the 1968 cohort. A surprisingly large share move into tenant co-operatives. Such moves, as well as moves into owner occupation, occurred mainly within Gävleborg County. Individuals moving to other municipalities outside the county moved to a larger extent into rental housing.     

Chlorobenzenes, chlorinated pesticides, coplanar chlorobiphenyls and other organochlorine compounds in Greenland biota

This paper summarises the levels and composition of chlorobenzenes, chlorinated pesticides, coplanar polychlorinated biphenyls (PCBs) and the chlorinated compounds octachlorostyrene (OCS), hexachlorocyclobutadiene (HCBD) and pentachloro-anisole (PCA) in biota from the terrestrial, freshwater and marine environment of Greenland. The data were obtained during the second phase of the Arctic Monitoring and Assessment Programme (AMAP). Of the chlorobenzenes, hexachlorobenzene was the main constituent detected in almost all samples. The chlorobenzenes accumulate in the marine food web in a similar manner to the better-studied persistent organic pollutants, with maximum concentrations in beluga, minke whale and narwhal. However, concentrations in ringed seals and kittiwakes were lower than in marine fish, contradicting biomagnification. Of the organochlorine pesticides, the drin pesticides (aldrin, endrin, dieldrin) and heptachlor had increasing concentrations along the food chain, whilst biomagnification was less pronounced for endosulfan, methoxychlor and mirex. Endosulfan and methoxychlor are pesticides still in use and considered less persistent than other organochlorine pesticides. Their occurrence in Arctic biota is of particular concern, also given the high acute toxicity of endosulfan to fish. Chlorobenzene and pesticide concentrations tended to be lower in the Greenland samples than in the same animals from the Canadian Arctic, whilst their concentrations were similar to samples from Svalbard and Iceland. However, temporal trends might overlap the geographical differences. Coplanar chlorobiphenyls (CBs) were found in all samples analysed, with the maximum concentrations found in marine mammals such as beluga and narwhal. Biota from the terrestrial environment appeared to be less contaminated. The main contributor on a TEQ basis was CB126. OCS, HCBD and PCA were detected in biota from Greenland, although at very low concentrations. OCS seems to have the widest occurrence and the highest potential for biomagnification of the three compounds analysed.